Journal of Alzheimer's Disease - Volume 33, issue 1

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ISSN 1387-2877 (P)

ISSN 1875-8908 (E)

Impact Factor 2018: 3.476

The Journal of Alzheimer’s Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease.

The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer’s disease.

Abstract: A majority of the genes linked to human disease belong to evolutionarily conserved pathways found in simpler organisms, such as Caenorhabditis elegans and Drosophila melanogaster. The genes and pathways of these simple organisms can be genetically and pharmacologically manipulated to better understand the function of their orthologs in vivo, and how these genes are involved in the pathogenesis of different diseases. Often these manipulations can be performed much more rapidly in flies and worms than in mammals, and can generate high quality in vivo data that is translatable to mammalian systems. Other qualities also make these organisms particularly well suited…to the study of human disease. For example, developing in vivo disease models can help illuminate the basic mechanisms underlying disease, as in vitro studies do not always provide the natural physiological complexity associated with many diseases. Invertebrate models are relatively inexpensive, easy to work with, have short lifespans, and often have very well characterized and stereotypical development and behavior. This is particularly true for the two invertebrate model organisms that this review will focus on: Caenorhabditis elegans and Drosophila melanogaster. In this review, we will first describe an overview of modeling Alzheimer's disease in flies and worms, and will then highlight some of the more recent advances that these “simple” animals have contributed to our understanding of Alzheimer's disease in recent years.
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Abstract: The long term effect of single (day 1) and twice (day 1 and 3) injections of intracerebroventricular (ICV) streptozotocin (STZ) at the doses of 1 and 3 mg/kg on the cognitive functions of male Wistar rats was evaluated. Elevated plus maze, passive avoidance, and Morris water maze tests were used to assess the cognitive functions. A significant cognitive deficit was found at the 2nd week onwards, which persisted up to the 14th week with single and twice ICV-STZ (3 mg/kg) injections, whereas no cognitive impairment was found in ICV-STZ (1 mg/kg) treated groups after 8–10 weeks.

Abstract: Genetic variants in the granulin (GRN) gene have been shown to increase the risk of Alzheimer's disease (AD). Here, we report that the A allele of rs5848 in GRN reduces plasma granulin levels in a dose-dependent manner in a clinically-defined AD sample cohort. Similarly, the mRNA levels of granulin were decreased with respect to A allele of rs5848 in the inferior temporal cortex of neuropathologically confirmed AD patients. Our findings suggest that the A allele of rs5848 is functionally relevant by reducing the expression of granulin.

Abstract: Recently, we demonstrated in endothelial nitric oxide synthase deficient (eNOS−/− ) mice that loss of endothelial NO led to increased protein levels of amyloid-β protein precursor (AβPP), β-site AβPP cleaving enzyme 1 (BACE1), and amyloid-β (Aβ) peptide. Therefore, our aim was to determine if NO supplementation in vivo would attenuate AβPP and BACE1 protein levels. cGMP levels were significantly increased while AβPP and BACE1 protein levels were statistically lower in cerebral microvessels from nitroglycerin-treated eNOS−/− mice as compared to vehicle-treated mice. Our findings support the concept that preservation of NO/cGMP signaling is an important modulator of expression and processing…of AβPP.
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Abstract: Epigenetic mechanisms such as histone-acetylation have been implicated with learning and memory and are believed to contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Histone-deacetylase (HDAC) inhibitors were shown to exhibit neuroprotective and neurodegenerative properties in AD animal models, and targeting HDACs appears to be a promising therapeutic strategy for brain diseases. The role of the distinct HDAC proteins in the adult brain is, however, not well understood and so far only pan-HDAC inhibitors have been tested in preclinical settings. Understanding the role of individual HDACs in cognition and AD pathogenesis is therefore vital to develop…more selective HDAC inhibitors for the treatment of AD. In this study we investigated the role of HDAC5 in memory function and AD pathogenesis. We show that loss of HDAC5 impairs memory function but has little impact on pathogenesis in a mouse model for amyloid pathology. Our data reveals a novel role of HDAC5 in memory consolidation and shows that future approaches to develop more selective HDAC inhibitors for the treatment of AD should avoid targeting HDAC5.
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Abstract: Microglia manage immunosurveillance and mediate inflammation, both suggested to be important in Alzheimer's disease (AD). The aim of this study was to investigate if microglial markers could differentiate, firstly between AD and controls, and secondly between stable mild cognitive impairment (MCI) and those progressing to AD and vascular dementia (VaD). Furthermore, we investigated if these markers were sufficiently stable to be used in clinical trials. We quantified YKL-40 and sCD14 in cerebrospinal fluid (CSF) from 96 AD patients, 65 healthy controls, and 170 patients with MCI from baseline and over 5.7 years. For the stability analysis, two CSF samples were…collected from 52 AD patients with a six-month interval in between. YKL-40, but not sCD14, was significantly elevated in AD compared with healthy controls (p = 0.003). Furthermore, YKL-40 and sCD14 were increased in MCI patients who converted to VaD (p = 0.029 and p = 0.008), but not to AD according to NINCDS-ADRDA. However, when stratified according to CSF levels of tau and Aβ42 , YKL-40 was elevated in those with an AD-indicative profile compared with stable MCI with a normal profile (p = 0.037). In addition, YKL-40 and sCD14 were very stable in AD patients with good correlation between time-points (r = 0.94, p = 3.4 × 10−25 ; r = 0.77, p = 2.0 × 10−11 ) and the cortical damage marker T-tau. Thus, microglial markers are stable and may be used as safety markers for monitoring CNS inflammation and microglia activation in clinical trials. Moreover, YKL-40 differentiates between AD and controls and between stable MCI to AD and those that convert to AD and VaD.
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Abstract: Brain plasticity and cognitive compensation in the elderly are of increasing interest, and Alzheimer's disease (AD) offers an opportunity to elucidate how the brain may overcome damage. We provide neurophysiological evidence of a short-latency event-related potential (ERP) component (C145) linked to stimulus relevancy that may reflect cognitive compensation in early-stage AD. Thirty-six subjects with early-stage, mild AD and 36 like-aged normal elderly (controls) had their EEG recorded while performing our Number-Letter task, a cognitive/perceptual paradigm that manipulates stimulus relevancies. ERP components, including C145, were extracted from ERPs using principal components analysis. C145 amplitudes and spatial distributions were compared among controls,…AD subjects with high performance on the Number-Letter task, and AD subjects with low performance. Compared to AD subjects, control subjects showed enhanced C145 processing of visual stimuli in the occipital region where differential processing of relevant stimuli occurred. AD high performers recruited central brain areas in processing task relevancy. Controls and AD low performers did not show a significant task relevancy effect in these areas. We conclude that short-latency ERP components can detect electrophysiological differences in early-stage AD that reflect altered cognition. Differences in C145 amplitudes between AD and normal elderly groups regarding brain locations and types of task effects suggest compensatory mechanisms can occur in the AD brain to overcome loss of normal functionality, and this early compensation may have a profound effect on the cognitive efficiency of AD individuals.
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Abstract: Mutations in the progranulin gene (GRN) were first implicated in frontotemporal lobar degeneration in 2006. The GRN p.Leu271LeufsX10 mutation is one of the most common GRN mutations worldwide. To gain further insight into the origin of this mutation in Italy, we performed a haplotype sharing analysis (32 families, residents of Lombardy) and refined the GRN p.Leu271LeufsX10 mutation dating. We showed that almost all families (30/32) can be traced to a single founder. We further estimated the age of this mutation using different methods and population growth rates both for Italy and Lombardy. Using DMLE, we dated the origin of this…mutation to the Middle Ages, at the turn of the first millennium (phased families only, Italy: 39 and Lombardy: 32 generations ago; all families Italy: 45 and Lombardy 38 generations ago). Mutation dating was slightly postdated using Estiage (phased families only: 15 generations ago; all families: 20 generation ago). From a translational perspective, targeting mutation carriers offers a unique model to test disease-modifying drugs in clinical trials.
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Abstract: Apolipoprotein E4 (ApoE4) is a major genetic risk factor for the development of Alzheimer's disease (AD). The aim of this work was to find if carrying ApoE4 alleles correlates with molecular changes associated with specific processes involved in AD pathophysiology and whether they are useful as early biomarkers of AD. Fifty four young healthy adults (aged 20–55) were recruited. Of these, 33 carried at least one ApoE4 allele and 21 did not (ApoE 3/3). We also recruited eleven patients with clinical diagnoses of probable AD and nine persons of similar age without dementia who served as controls of the AD…patients. Using peripheral lymphocytes, we measured RNA expression of glycogen synthase kinase 3β (GSK3β), the regulator of calcineurin 1 (RCAN1), calcineurin, and RNA-dependent protein kinase (PKR) by PCR and protein levels of RCAN1, calcineurin, GSK3β, and phospho-tau by western blotting. Young healthy persons carrying the ApoE 4/4 genotype express more RNA for RCAN1, calcineurin, and PKR and higher protein levels of calcineurin, RCAN1, GSK3β, and phospho-tau than controls (ApoE 3/3). Moreover, we found that carrying one or two alleles for ApoE4 is associated with subjective cognitive impairment. We conclude that lymphocytes from young, non-demented persons carrying the ApoE 4/4 genotype show molecular changes that are involved in specific processes associated with the pathophysiology of AD such as increased phosphorylation of tau or increased expression of stress-related proteins like calcineurin, GSK3β, or RCAN1. These changes may help to understand the development of AD and in the early diagnosis of the disease.
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